The chemotherapeutic failure or on the other name chemotherapeutic resistance : is when the host cell can evade (resist) the
effects of chemotherapeutic agent. It is one of the most problem in chemotherapy.
Chemotherapy resistance can be divided into 2 main factor: firstly, host -related factors. The second one
is tumor related factor, which is reflected the effect of chemotherapeutic by
the mechanism of efflux- pump that handle the expression of drug .
Host Related
factors
Pharmacokinetic
is an effects of host-related factors that can determine the activity of the
drug . it is defined as the what body do to the drug and can be divided into 4
situation : absorption, distribution, metabolism and excretion (ADME). The host mechanism that reflected the effective of chemotherapeutic drug, by
prevent reaches its target or prevent to
fulfill its intended goal is “Pharmacokinetic resistance ” . (Drugs
must target the tumor site to kill the
micro-organism).
Absorption
: it can reduce the effect of the drug by reducing the bioavailability
of it. Then, cause failure of drug effect this occur by permeability
glycoprotein that found in (GIT)including the small intestine. P-gp can
reflected the chemotherapeutic effect by reducing the oral bioavailability of
drugs . this is by overexpression of P-gp that results in bioavailability
reduction of several these agents. Also, food is another example which can affect the drug absorption
and bioavailability. Highly fat meal can affect the drug bioavailability and
decrease the affect .
Metabolism
There
are 2 steps of drug metabolism , the first step is involve reactions of hydroxylation or
oxidation. metabolism enzymes such as CYP450 and glutathione S–transferase
could be lead to inactivattion certain anti- tumor drugs. Introducing polar
groups into xenobiotic groups occur by CYP450 enzyme. Overexpression of CYP450 in cancer patients
might lead to resistance due to the rapid inactivation of the drug. Glutathione
S Trans-ferase also another enzyme that
could contribute the resistance of chemotherapy. it responsible in the second
step of drug metabolism, the resistance occur when overexpression of this
enzyme (same CYP450) . This resistance could occur by metabolizing the drugs
into inactive form .
Excretion
It is the final rotation of the drug in the
body . it can by two mechanism : biliary and renal excretion. The change rate of glomerular filtration rate
(GFR) can effect of drug availability and bioavailability which can contribute
to the resistance of chemotherapeutic .
Drug–drug interactions
Usually , the combine of two or more
of chemotherapy is good in treat the infection. Conversely, it sometimes that
co-administration of drugs may lead to antagonism, one drug may counteract the
other one. Lately, Sodium
bicarbonate has been used systemically in the treatment of cancer. By induces
systemic alkalosis, it can enhance methotrexate excretion by elevation of urine
pH. Therefore, sodium bicarbonate modulates the pharmacokinetics of
methotrexate. Tamoxifen is another drug
that can decreased their activity by drug-drug interaction . it is a pro-drug that needs to be metabolized to its
active form by CYP2D6 and other . Some drugs, particularly from the group of
SSRI, inhibit CYP2D6 and so reduce the efficacy of Tamoxifen by decreasing
amount of its active metabolites. A combination of clindamycin and macrolides
drug class can antagonize each other.
Tumor
related factors
Sometime the failure of chemotherapy
to treat associated with the tumor site. Could be by Evolutionary resistance
or acquired resistance . The resistance
that can be found in bacteria due to exposure to antibiotics is called acquired resistance. it could be either through altering its site of
action or interfering with drug resident.
Altering drug site
it is occur when the drug reached its
target lead to altering the site of drug which lead then to the resistance . the
example is methotrexate. It is a drug of choice for the treatment of several
types of tumors. The mechanism of methotrexate inhibition of the dihydrofolate reductase enzyme (DHFR) this inhibition of the
DHFR lead to inhibit the tumor cells. Researches show that the DHFR can reflected the
methotrexate by generating extra copy of its
which means that producing more copy
of dihydrofolate reductase enzyme. Also, there is another example which can reflected
their effect by altering the site of it. Fluorouracil which its MOA is thymidylate synthetase
inhibitor and it used in several types of tumors. It has shown that the more production of extra copies of that
enzyme can contribute the resistance to
the drug.
Alteration of drug residency in
cancer cells
P-glycoprotein It is a glycoprotein
which is localized at the plasma
membrane of colon, jejunum, bile
canaliculi and the other . it is consider as enzyme inducer of CYP3A4. This expression of CYP3A4 can decreased
the activity of some chemotherapeutic such as (cyclosporin,Tamoxifen). This is
explain the altering drug residency.
Microenvironmental
resistance (Trapping mechanism)
The micro environmental of the
tumor can make failure to chemotherapeutic
by reducing the activities of it this lead to causing fail in responses of the drug. This is by two
mechanism : one of it through disturbing drug partitioning, the
second is through induction of multi
drug resistance expression. It is prevented chemotherapeutic to reaching their
targets site . Because the weakly acidic
drugs increase their dividing into the
interstitial fluid, which is alkaline media this prevented from reaching their targets.
chemotherapy could impacted their activity and contribute in drug
resistance by the physics of the tumor site. There are 2 mechanism in which Tumor
can decreased the amount of drug to reaching its target either by clonal tumor
expansion or by the tumor perfusion .
This is called interacting of humor- host factor
